Bone Mar row Patholog y

1 t r a P

R.S. Riley , M.D., Ph .D.

Bone Marrow Pathology

Bone marrow basics Red cell diseases White cell diseases Other diseases

Bone Marrow Pathology

Bone marrow basics
Hematopoiesis Bone marrow structure Obtaining bone marrow Interpreting bone marrow

Red cell diseases White cell diseases Other diseases

The bone marrow, stupid!

Where do blood cells come from?

Bone Marrow: The Seedbed of Blood

The present work intends to

demonstrate the physiologic importance of the bone marrow and that it is an important organ for blood formation which has not been recognized. It operates continually in a de novo formation of red blood cells

Neumann, E. Du role de la moelle des os dans la formation du sang. C. R. Acad. Sci. (Paris) 68:1112-1113, 1869

Ernst Neumann (1834-1918)

The Common Ancestral Cell

Stem cell - Cell type that can maintain its own numbers by cell division and yet provide descendants that eventually mature into the various blood cells The great debate Dualist concept of Ehrlich Monophyletic theory of Pappenheim Debate lasted four decades

Artur Pappenheim (1870-1916)

Bone Marrow Cell Culture

Hematopoiesis
Hematopoietic stem cell Mophologically unrecognizable Undergo self renewal Capable of multilineage maturation Express stem cell antigen (CD34) Committed progenitor cell Mophologically unrecognizable May lack self renewal Irreversible lineage committment Express CD34, CD38, HLA-DR Blast cell First recognizable cell in lineage Mitotically active Mature cell Functionally active Mitotically inactive Erythroid, myeloid, megakaryocytic lines + lymphocytes, plasma cells, etc.

Hematopoietic stem cell

Committed progenitor cell

Blast cell

Mature cell

Amplification During Hematopoiesis

og c e niz le b a

R
Stem Cell

Loss of proliferative potential Biochemical changes

Surface markers Receptors Adhesion molecules

m Co
Stem Cell
2 4

tt i m
8

ed

16

32

64

128

256

512

1024

Chromatin openness Access to epigenetic transcription factors

Regulated by the hematopoietic cytokines Tremendous reserve to respond to disease states

Loss of proliferative potential

Stem Cells - Self Renewal vs. Differentiation

Parent Stem Cell

Renewed Stem Cell

Committed Differentiating Cell

Telomerase

No Telomerase

Renewed Stem Cell

Fully Differentiated Cell

NK Cell Plasma Cell B Cell Neutrophil Monocyte

T Cell Precursor Thymus

Lymphoblast

Myeloblast

Eosinophil

Lymphoid Progenitor Cell

Myeloid Progenitor Cell

Basophil

Multipotent Stem Cell Helper T Cell Suppressor T Cell

Megakaryocyte Platelets Hematopoietic Stem Cell Erythrocyte

Hematopoiesis (Greatly Simplified)

NK Cell Plasma Cell B Cell Neutrophil Monocyte

G-CSF
Lymphoblast Thymus Myeloid Progenitor Cell

IL-2

M-CSF
Myeloblast

IL-5

Eosinophil

Lymphoid Progenitor Cell

G-CSF TPO GM-CSF

Multipotent Stem Cell Basophil

EPO

Helper T Cell

Suppressor T Cell

IL-1

IL-3 SCF
Hematopoietic Stem Cell Megakaryocyte Platelets Erythrocyte

IL-1 TNF

Hematopoiesis
Hematopoietic Cytokines

Hematopoietic Cytokines
Factor Stem cell factor (SCF) IL-3 GM-CSF G-CSF M-CSF IL-5 Erythropoietin (EPO) Thrombopoietin (TPO) IL-6 IL-2 IL-1, TNF Major Site of Action Pluripotent cells Early progenitors (CFU-GEMM) Myeloid progenitors (CFU-GM) Granulocyte precursor Monocyte precursor Eosinophil progenitors Erythrocyte progenitors Megakaryocyte progenitors B cell precursors T cell precursors Stromal cells

Lajtha, L.G. The Common Ancestral Cell, 1980

Scanning Electron Micrographs of Hematopoiesis

Erythropoiesis
Regulated primarily by erythropoietin (EPO) Erythroblasts - all erythroid precursors Five generations can be recognized Erythroblastic island - Macrophage + associated erythroblasts, nonparatrabecular Morphologic features Occur in islands Adhere tightly to each other Round nuclei Clumped chromatin, basophilic cytoplasm Immature, homogenous in rapidly regenerating or diseased marrows

Bone Marrow
Stem Cells

Regulation of Erythropoiesis

Reticulocytes

Erythropoietin

Red Cell Mass

O2 Delivery
Cadiopulmonary function Hgb Concentration O2 Affinity Atmospheric O2 Blood Volume Other Influences

Kidney
O2 Sensor

EPO Production

M ye lo bl as t

Stem Cell

Pr o

no r

R et ic ul oc yt e

ob la

st

Er yt hr oc yt e

B N as or o m ph ob ili la c st Po l yc N hro or m m a ob to la ph st il O rt N hoc or h m ro ob m la ati st c

Primary Site of EPO Action

ic

Normal Erythropoiesis

Granulopoiesis
Four generations of cells Adults produce 1-2 x 109 granulocytes/ day Progressive nuclear segmentation, acquisition of primary and secondary cytoplasmic granules Myeloblasts adjacent to bony trabeculae or arterioles Regulated by GM-CSF, G-CSF, IL-3, IL-5, etc. Mature granulocytes excrete regulatory substances that inhibit granulopoiesis

M ye lo bl as t

Stem Cell

(P Pro ro m gr ye an lo ul cy oc te yt e) N e M utr ye o lo ph cy ili te c M Ne et ut am ro ye ph lo ilic cy te

Se N gm eu e tr nt op e hi d l

N eu t B rop an h d ilic

Granulopoiesis

Megakaryopoiesis
Endomitotic synchronous nuclear replications

2N

4N

8N

16N

32N

Differentiation and cytoplasmic granulation

Platelet shedding

Platelet Kinetics
67% in peripheral blood

33% in spleen

Life Span- 8-10 Days